Recessive Epilepsies Generally Cause Complete Loss of Function (Null Alleles)
In recessive epilepsies, pathogenic variants are required on both alleles (i.e., biallelic) for the condition to manifest; these variants can be the same (i.e., homozygous) or different (i.e., compound heterozygous).
With rare exceptions, recessive pathogenic variants in epilepsy tend to be loss-of-function. These variants are often alterations to the amino acid sequence that introduce a premature truncating codon resulting in a degradation of the mRNA transcript in the cell through the process of nonsense-mediated decay (NMD). Occasionally, NMD may not be activated, and the transcript can code for a shortened protein that is generally non-functional. Truncating variants include nonsense, frameshifts, and variants at the donor/acceptor splice site that generally result in frameshifts. Missense variants can also result in loss-of-function if they affect protein function, often if they occur in a conserved domain, leading to an unstable protein or otherwise affects the tertiary structure of the protein. The net result of truncating or missense loss-of-function variants inherited in a recessive manner is that the proband essentially has no or very little functional protein, while parents with 50% residual protein levels are unaffected. Thus, any therapeutic approach that restores protein levels to ~50% will be an effective strategy (Fig. 1).
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